ABERRANT RET RECEPTOR EXPRESSION IN THE MAMMARY GLAND CAUSES TUMORS AND DEVELOPMENTAL DEFECTS

ALBANA GATTELLI; TOM ROLOFF; ROBERT CARDIFF; CHARLES PEROU; EDITH C KORDON; LEWIS CHODOSH; NANCY E. HYNES

Congreso; LXI Reunión Anual SAIC; 2016

The receptor tyrosine kinase (RTK) Ret, a key oncoprotein inthyroid carcinomas due to gain-of-function mutations, has alsobeen implicated in other types of cancers. Recently, Ret copynumber gains and mutations have been reported at low frequenciesin breast tumors. Furthermore, we and others have reportedthat Ret is overexpressed in about 40% of human tumors and thiscorrelates with poor patient prognosis. Using a transgenic mousemodel with the MMTV promoter controlling Ret expression in thedoxycycline-inducible system, we show that overexpression ofwild type (WT) Ret in the mammary epithelium produces hyperplasiasand mammary tumors displaying a solid morphology thatrecapitulates features of human solid ductal carcinoma in situ.Moreover, Ret-induced tumors express ErbB2 and are estrogenreceptor positive. Importantly Ret-induced tumors rapidly regressafter doxycycline withdrawal indicating that Ret is the driving oncoprotein.Using next generation sequencing (NGS) we examinedlevels of transcripts in these tumors. We found that Stat signalingpathways could contribute to Ret-driven tumorigenesis. It is wellknown that RTKs, which are implicated in breast cancer, e.g. theErbB receptors, also have roles in normal development. We foundthat Ret is highly expressed in mid-lactation. Indeed, Ret appe arsto have a role in the post-lactation transition to involution, whereStat pathways are crucial. Interestingly, when Ret is inducedearly in lactation we observe enhanced kinetics of involution. Theinvolution period is well known to drive cancer progression. Thus,our results suggest that if Ret expression is deregulated duringthe lactation-involution transition this might contribute to breastcancer development.